Drugs for

Heart Failure
Medical students (Sem 3)

DR. NORLIANA MASBAH

DEPT OF PHARMACOLOGY
Learning outcomes
Basic pathophysiology of heart failure
Compensatory mechanisms in heart failure
Objectives of treatment
Drugs for heart failure :
Mechanism of action (MOA)
Examples/classification
Pharmacological properties
Adverse effects
Clinical indications
Definition

inadequate cardiac
output to meet the
metabolic need of the
body
Heart
Failure Cardiac output (CO): volume of
blood pumped by the heart
during systole
 Factors affecting CO

CO = Heart rate (HR) x

Stroke volume (SV)

Preload: amount of ventricular stretch at the end of diastole

Afterload: resistance that must be overcome by the heart in
order for the ventricle to eject blood
Contractility: the force of contraction
Heart rate: increase HR, increase CO
Pathophysiology of Cardiac Failure

LEFT VENTRICULAR DYSFUNCTION/FAILURE

Pressure Loss of Impaired

Volume overload
functional contractility
(valve overload myocardium (cardiotoxic
incompetence) (hypertension) (IHD, MI) drugs)

LV dysfunction Left ventricular end diastolic

pressure (LVEDP) Or Preload
CO
due to amount of blood in
ventricle

left atrial pressure &

Global pulmonary capillary
hypoperfusion pressure

pulmonary pressure
forces fluid out of
Clinical symptoms pulmonary capillaries
of LHF : dyspnea & pulmonary congestion
pulmonary odema
RIGHT VENTRICULAR DYSFUNCTION/FAILURE
Commonest cause: LV
failure, others:
cardiomyopathy

in amount of blood in
ventricle R atrial
RV dysfunction pressure

pressure in vena cava

system impaired venous
drainage from the body

pressure in liver, GIT and

lower extremities

Clinical symptoms of RHF:

hepatomegaly, abd
pain/distention & peripheral
odema in lower limbs
Compensatory mechanisms in HF
A means of the failing heart to CO.
Initially beneficial, but these alterations leads to further
deterioration of cardiac function.
Activation of Renin-angiotensin-
aldosterone system (RAAS)
CO -due to blood flow to kidneys

sympathetic activity
Renin release
angiotensin II
Heart rate & Vasoconstriction: formation
myocardial enhances venous
contractility return & cardiac
preload
Na & H20 Stimulate Vaso
retention by aldosterone constriction
Heart size kidneys release by in blood
ventricles Also afterload adrenals vessels
dilate -->
elongated
heart fibres afterload
weaker blood vol - if heart ( due to
contractions ejection peripheral
unable to pump extra vol
fraction & peripheral & pulmonary resistance)
CO odema occur
Cardiac remodeling
Objectives of Treatment

Tx Objective

preload /
Inotropic Volume overload Prevent
(oedema,SOB)
afterload(or
state both) remodeling

-Diuretics

Inotropic -ACE Most heart

Agents Inhibitors/ARB/ failure drugs
Beta blockers
aldosterone
antagonist
Drugs for Cardiac Failure
Inhibitors of renin-angiotensin-
aldosterone system (RAAS)
1.ACE inhibitors (ACE-I) Inotropic
2. Angiotensin receptor blockers agents
(ARB)
3. Aldosterone antagonists

Vasodilators
(arterial dilators) & Diuretics Beta Blockers
venodilators
 A) Inhibitors of RAAS
1) Angiotensin-converting enzyme(ACE) inhibitors , ACE-I
MOA:
1) Inhibits the angiotensin-converting enzyme (ACE) which cleaves angiotensin I to form
angiotensin II
2) Inhibit degradation of bradykinin (a potent vasodilator) vasodilate reduced
peripheral vascular resistance
3) Reduce long term remodeling of the heart
Reduced preload and
Angiotensinogen afterload of the heart
(in liver) CO
Renin (from
kidney)

Angiotensin I
cardiac
ACE- Angiotensin afterload work
Inhibitors converting enzyme vasoconstriction CO
Angiotensin II Stimulate Stimulate plasma
aldosterone release kidneys to retain vol
Na+ & H20 preload
Stimulate release of
ADH hormone from H20 cardiac
pituitary retention workload
 Examples:
Captopril, Perindopril, Enalapril, Ramipril, fosinopril, lisinopril
quinapril , moexipril (all are prodrugs except captopril & lisinopril)

Pharmacokinetics:
Oral mostly/IV administration (only enalapril)
food may absorption of captopril
Most ACE-I eliminated by kidneys (except fosinopril & moexipril)

Adverse effects:
Persistent dry cough (commonest) bradykinin
hypotension Important drug
interactions:
Hyperkalaemia K+ sparing
Acute renal failure/renal insufficiency diuretics,
aldosterone
Angiodema (rare) antagonists or K+
Teratogenic contraindicated in pregnancy supplements
2) Angiotensin receptor blocker (ARB)

MOA:
Block the angiotensin II (Type 1) receptors on blood vessels
No effect on bradykinin metabolism
More selective blocker of angiotensin pathway
Produce similar effects as ACE-I
preload & afterload hence CO.
Examples: Losartan, Valsartan, Candesartan, irbesartan,
telmisartan, olmesartan
Oral administration
Indication: as an alternative in heart failure patients who is
intolerant to adverse effects of ACE-I
Adverse effects
Similar to ACE-I
However causes less cough and angioedema (as do not affect
bradykinin levels)
3) Aldosterone antagonists
MOA:
Blocks the aldosterone receptors prevents binding of
aldosterone inhibit aldosterone-mediated Na+ & water
reabsorption
Effects: promotes salt and water excretion (reduces odema)
Example: spironolactone
Also work as a potassium-sparing diuretic
Pharmacokinetic: Oral administration, renal elimination
Adverse effects:
GIT upset
hyperkalaemia
Anti-androgenic effects: gynaecomastia (males), irregular menses,
hirsutism(females)
Indication: can be combined with other diuretics (eg. Thiazide
or loop diuretics which usually causes K+ excretion) to prevent
hypokalaemia
B) VASODILATORS

Type of vasodilator Examples

Arteriolar/arterial dilator Hydralazine
(vasodilator)
Venodilator Isosorbide dinitrate
Mixed Sodium nitroprusside
ACE-inhibitors

Useful in heart failure because they work by:

preload (through venodilation)
afterload ( systemic arteriolar resistance through
arteriolar dilation)
OR BOTH (vasodilate & venodilate)
1) Arterial dilator
Example: hydralazine (oral or IV)
MOA: reduce systemic vascular resistance afterload hence
improves CO
Usually for patients with poor CO when fatigue is predominant
symptoms

2) Venodilator
Isosorbide dinitrate (ISDN)
MOA: venodilation preload by increasing venous
capacitance (pooling of blood in peripheral veins hence
ventricular volume)
Oral administration
Usually prescribed for HF patients with predominant pulmonary
edema
* Combination of both hydralazine + ISDN : effective & improve
survival in patients who are stabilised on ACE-I/B blocker)
3) Mixed arterial and venodilator
Sodium nitroprusside
Parenteral administration: usually IV
MOA: reduces both preload and afterload hence
increase CO

Nitroglycerin
Parenteral administration
Low infusion dose: selective venodilator
High infusion dose: can also act as arterial dilator

Adverse effects for all vasodilators/venodilators:

-headache, orthostatic hypotension, tachycardia
C) INOTROPIC AGENTS

Agents that increase myocardial contractility thus cardiac

output

Examples:
1) Cardiac glycosides (Digitalis) : Digoxin
2) 1 agonists: Dobutamine, Dopamine
3) Phosphodiesterase inhibitors: Milrinone, Inamrinone
Mechanism of inotropic action
-Increase cAMP
-Increase Ca2+ influx into
Inhibit Na+/K+/ATPase
myocardium
enzyme
(1 Agonist &
(Digoxin)
Phosphodiesterase inhibitors)

Increase
intracellular
Ca2+

myocardial
contractility

Inotropes (except digoxin) : associated with survival

(HF d/t coronary artery disease) usage limited in hospital
setting, short term
1) Cardiac glycosides: Digoxin

a) MECHANICAL EFFECT: Increase cardiac contractility

1) Inhibits Na+/K+/ATPase enzyme in the cardiac cell membrane
2) Reduced capacity of myocyte to pump Na+ out of cell
3) Rise in intracellular Na+ concentration gradient across cell
membrane (to drive Ca2+ out)
4) Hence less Ca2+ efflux via the Na+/Ca2+ exchanger
5) Rise in intracellular Ca2+ more Ca2+ interact with contractile
protein, actin & myosin
6) cardiac contractility, CO
 B) Electrophysiological effects
i) digoxin automaticity & prolongs
ventricular
refractory period (due to vagal i.e
rate , useful in
parasympathetic tone)
AF
ii) On AV-nodal conduction system
slows done AV conduction

C) Neurohormonal effects
- Exact mechanism unclear
- Proven that digoxin inhibits HR (reduce
sympathetic nervous system workload of
activation & increase vagal heart)
tone
Atrial fibrillation
Why we need to treat?
In AF : there is in atrial rate
Untreated AF -rapid ventricular rate (VR)
120-150/min
leads to reduce ventricular filling time
Reduce CO
Aim of tx is to:
reduce the high VR
Slow down AV conduction:
reducing conduction velocity
Prolongation of refractory period
DIGOXIN (cont)
Oral/IV preparation
Oral absorption good
Pharmacokinetics:
Elimination : kidney dose adjustment in renal dysfunction
Long half life : 36-40 hours (Once daily dose)
Loading dose - rapid onset (eg symptomatic atrial fibrillation)
Has low therapeutic index - toxicity
Adverse effects:
Digoxin toxicity - commonest :
Early indicators : GIT upset -
Nausea,vomiting,anorexia,diarrhea, Blurred vision,
yellowish vision (xanthopsia)
Arrythmias ca2+ overload
CNS: disorientation, hallucinations, confusion
Factors affecting digoxin toxicity
Hypokalaemia increased effect of digoxin on
Na/K+/ATPase) more binding site for digoxin on the
enzyme.
Caution if concomitant therapy with thiazide or loop
diuretics
Renal impairment
Hypercalcaemia, Hypomagnesaemia, hypothyroidism

Management of digoxin toxicity

Withhold the drug
Serum K+ monitoring replenish K+ if needed
ECG monitoring
Severe toxicity with ventricular arrythymias :
antiarrythmic drugs
Consider antibodies to digoxin (Digoxin immune Fab):
binds and inactivate digoxin
Digoxin clinical indications
Controversy - Limited benefits,
recognised side effects
Indication:
Not usually indicated in mild-mod
HF often respond to other drugs
HFpatients in atrial fibrillation
control Vent. Rate
HF patients in sinus rhythm (severe
HF) not responding to maximal
therapy with ACE-I,B blocker,
diuretics
2) 1 agonists
Example:
Dobutamine (widely used selective 1 agonist)
lead to contractility and CO
dopamine (non selective - 1, D1, 1&2) usually in
acute HF if need to raise BP - renal blood flow,
contractility and CO (at higher dose)
Both parenteral agent (IV infusion)
Has positive inotropic effects and causes vasodilatation
Indication: minimal role for chronic heart failure, mainly
for short term use of acute heart failure in the hospital/ICU
setting
Adverse effects:
Mainly tachycardia (more with dopamine) &
arrythmias
 1
3

2
4

MOA: bind to beta adrenergic receptor increase

intracellular cAMP protein kinase activation
phosphorylation of slow Ca2+ channel increase Ca2+
influx into myocyte increase myocardial contraction
3) Phosphodiesterase inhibitors

Examples: Milrinone, Inamrinone

Parenteral administration
MOA:
Heart: increase intracellular cAMP increase Ca2+
influx cardiac contractility.
Peripheral vasculature: vasodilation & venodilation.
Reduce afterload and preload
Indication: acute cardiac failure
Adverse effects:
Nausea, vomiting, arrhythmias,
thrombocytopenia,altered liver enzymes
Milrinone: less bone marrow & liver toxicity
D)Beta blockers
Has negative inotropic effect on the heart
(Therefore it was once considered to be
contraindicated in HF)
Recent studies had shown that -blockers:
Improved symptoms and survival of patient
with HF
Improves systolic function
Reverse cardiac modeling in HF
Examples:
Carvedilol (non selective )
Bisoprolol, metoprolol (1 selective blocker)
Possible mechanisms of beneficial
effects of blockers
1. Inhibit changes that occur due to chronic
activation of the sympathetic nervous system in HF
patients
2. Reduce work of heart by reducing heart rate
3. Inhibit renin release by kidneys
4. Reduce adverse effects of high concentration
of catecholamine on cardiac muscle fibers -
remodeling/hypertrophy of cardiac muscle
 Cardiac remodeling
chronic hemodynamic stress - alters
the shape, size, structure & function of
the ventricles
heart becomes more spherical
failing heart enlarges to ventricular
volume
Myocardium thickness also
increased contractility
Ventricle cont to enlarge &
myocardium hypertrophies l
increased cardiac wall tension &
fibrosis also myocardial tissue
apoptosis (death)
Eventually contractility impaired
Progressive process & detrimental
Adverse effects:

Bradycardia, fatigue
vivid dreams
cold hands
orthostatic hypotension & dizziness (alpha 1 blockade)

Guidelines for B-blocker initiation therapy

Therapy started cautiously at low dose, monitored

frequently, titrate up
Patients must be stabilized first with ACE/diuretic
E) Diuretics

MOA: promote diuresis circulating plasma

volume venous return to the heart (preload)
reduced blood vol & venous pressure

Reduce peripheral odema , pulmonary congestion

in HF, symptoms of volume overload

Clinically useful for patients with symptoms of

volume overload : orthopnea, paroxysmal nocturnal
dyspnoea
Types of diuretics used in HF
Thiazide diuretics Loop diuretics
-Furosemide
-hydrochlorothiazide torsemide, bumetanide

Potassium-sparing diuretic
(aka aldosterone
antagonist)
-spironolactone

General MOA: inhibit reabsorption of Na+ in the kidney

tubule hence resulting in retention of the Na+ ion (with
H20) in the tubule increased vol of urine diuresis
 Loop diuretics

Most commonly used in HF

eg Furosemide, torsemide, bumetanide
Oral and parenteral
MOA: inhibit reabsorption of Na+ via the
Na+/K+/2Cl- cotransport in ascending loop of
Henle decreased Na+ reabsorption
diuresis
Most potent diuretic - act where 25-30%
reabsorption of Na load occur
Rapid onset of action especially IV. Short
duration of action (2-4 hrs)
Thiazide diuretics

MOA: inhibit Na+/Cl- cotransporter in the

distal convoluted tubule increase
secretion of Na+ in the tubular fluid

Eg: hydrochlorothiazide (HCTZ) oral ,

chlorothiazide (IV/oral) , indapamide

Indication: additional agent if further diuresis

needed following loop diuretic
K+-sparing diuretics
Act at the collecting duct. 2 different MOAs:
Via acting as aldosterone antagonist : spironolactone,
eplerenone. Inhibit Na+ reabsorption, at the same time
retain K+
Inhibit Na+ influx via ion channel in the luminal
membrane amiloride, triamterene

Indications:
Spironolactone reported to reduce morbidity & mortality
in HF via preventing Na reabsorption, and prevents
aldosterone-induced fibrotic changes in myocardium
Given together with loop/thiazide diuretics to prevent
hypokalemia
 Diuretics: adverse effects
Loop diuretic Thiazide diuretics K+ sparing diuretic
(aldosterone)
Ototoxicity Hypercalcemia inhibit Hyperkalaemia (promote
reversible/permanent secretion of Ca2+ by Na+ excretion due to
kidneys inhibition of aldosterone,
retain K+)
Hypokalaemia (loss of K+) : heavy load of Na+ in Lethargy
collecting duct increased Na+ reabsorption in the
duct K+ excreted out in exchange for Na+
may need pre-tx monitoring, K+ supplementation
Acute hypovolaemia volume depletion Gastric upset - nausea

Hyperuricaemia (compete with uric acid for Gynaecomastia,

secretion via the organic acid secretory system) impotence (males)
Hypomagnesemia Hyperglycaemia impaired Hirsutism, menstrual
insulin release & tissue irregularities (females)
uptake of glucose
Hyponatremia: elevated ADH
following hypovolaemia